OVERVIEW: What every practitioner needs to know

Are you sure your patient has histiocytosis/hypophysitis? What are the typical findings for this disease?

Hypophysitis is a rare inflammatory disorder involving the pituitary gland, often presenting with visual complaints, headache, and/or hypopituitarism, as well as a sellar mass. Lymphocytic hypophysitis is the most common form, followed by granulomatous hypophysitis and xanthomatous hypophysitis.

Lymphocytic hypophysitis can be confined to the anterior pituitary, causing anterior pituitary hormone deficiency, or it can primarily involve the infundibulum and posterior pituitary, causing diabetes insipidus (DI) and hyperprolactinemia. Lymphocytic hypophysitis can also involve the entire pituitary and stalk, resulting in a combination of diabetes insipidus and anterior pituitary deficiency.

Langerhans cell histiocytosis (LCH) is a rare disease involving clonal proliferation of bone marrow–derived histiocytes (activated dendritic cells or macrophages). LCH may present as involvement of a single site (skin, bone, or lymph nodes) or as multisystem disease. Single-site involvement of the skull can result in DI. Multisystem disease can present with DI and can also manifest anterior pituitary hormone deficiencies.

Findings in hypophysitis

Children and adolescents with lymphocytic hypophysitis may present with signs of increased intracranial pressure, such as vomiting, headaches, and visual disturbances. At presentation, varying degrees of hypopituitarism may be seen. The severity and frequency of headaches, the most common symptom, do not correlate with pituitary size.

Most patients with lymphocytic hypophysitis have either partial pituitary hormone deficiency or panhypopituitarism. Although corticotrophs and thyrotrophs are most often affected in adults, DI appears to be the most common hormonal deficiency in children, followed by growth hormone deficiency. Children may also present with secondary hypothyroidism, adrenal insufficiency, and hypogonadism; less frequently, hyperprolactinemia is seen.

Findings in histiocytosis

Single-site disease: Lytic lesions of the skull can be associated with DI.

Multisystem disease: DI is the most common endocrinopathy in LCH and the presenting symptom in approximately 4% of patients with LCH . The majority of patients with LCH and DI will have other anterior pituitary hormone deficiencies.

What other disease/condition shares some of these symptoms?

Symptoms of hypophysitis may overlap with other disorders affecting the pituitary, such as pituitary adenomas and craniopharyngiomas. All three diseases can present with symptoms of increased intracranial pressure and varying degrees of pituitary hormone deficiency.

In addition to histiocytosis, pituitary adenoma, craniopharyngioma, and trauma may also cause DI. Two other histiocytic conditions, juvenile xanthogranuloma and Erdheim-Chester disease, can also mimic skin findings of LCH.

What caused this disease to develop at this time?

The cause of lymphocytic hypophysitis is not known but is suspected to have an autoimmune basis. Although adults and children with lymphocytic hypophysitis are at increased risk of a coexisting autoimmune disorder, the presence of antipituitary antibodies lacks specificity for hypophysitis.

The cause of LCH is unknown. Attempts to identify a viral cause have yet to identify a viral trigger, although it is thought to be an autoimmune disorder.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The diagnosis of lymphocytic hypophysitis should be suspected in a patient with symptoms of increased intracranial pressure, characteristic findings on magnetic resonance imaging (MRI), and pituitary dysfunction. Laboratory studies should be directed at identifying DI, hyperprolactinemia, and deficiencies in growth hormone, adrenocorticotropic hormone, thyroid-stimulating hormone (TSH), and gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

Diagnostic evaluation of any patient with LCH should include complete blood count, bone marrow aspirate and biopsy, skeletal survey, skull series, bone scan, and chest radiography. Specific imaging is required based on other presenting symptoms, including MRI of the brain for patients with DI with or without anterior pituitary hormone deficiencies.

DI may be suspected based on a history of increased thirst and urination. Initial evaluation should consist of serum electrolyte, glucose, urea, creatinine, and phosphate levels; osmolality; as well as urine osmolality and specific gravity. A water deprivation test may be needed to more clearly identify DI.

As prolactin can be released in response to stress (i.e., induced by venipuncture), it may be beneficial to draw blood for a prolactin level 20-30 minutes after placing an intravenous line for drawing blood.

Evaluation of anterior pituitary hormones should include TSH, free or total T4, insulin growth factor 1 (IGF-1) and cortisol levels. Growth hormone deficiency should be screenedwith IGF-1, not random growth hormone, as growth hormone secretion is pulsatile and frequently not detected in normal individuals. Testing of gonadotropins LH and FSH should be performed in individuals with suspected hypogonadism.

Would imaging studies be helpful? If so, which ones?

In the majority of patients with hypophysitis, MRI can identify a homogeneously enhancing pituitary mass extending into the suprasellar area. Other findings include a thickened infundibulum and loss of posterior pituitary hyperintensity. In children, MRI findings may be normal at initial presentation and may not demonstrate characteristic findings until months after onset of symptoms and hormone deficiency.

MRI findings that distinguish hypophysitis from macroadenoma include symmetric enlargement of the gland and homogeneous enhancement with gadolinium. The dura mater adjacent to the mass in lymphocytic hypophysitis can show a unique, marked enhancement in contrast known as a "dural tail."

Brain MRI findings in LCH characteristically show a thickening of the pituitary stalk in patients with DI.

If you are able to confirm that the patient has hypophysitis or Langerhans cell histiocytosis, what treatment should be initiated?

As the natural history of lymphocytic hypophysitis is variable and unpredictable, appropriate treatment is controversial. In some cases, attenuation of inflammation and return of pituitary function has been documented after treatment with corticosteroids. Other studies have shown either failure of improvement in symptoms or relapse when therapy was discontinued. Surgical decompression of the mass is indicated if conservative therapy fails or if signs of optic nerve compression are present.

Optimal treatment of LCH has yet to be determined. Clinical trials have examined outcomes in patients treated with chemotherapeutic combinations and are ongoing. Treatment approaches are stratified into low-risk disease, multisystem disease with risk of organ involvement (lung, liver, spleen, bone marrow), or central nervous system LCH. Hematopoietic cell transplantations have also been performed in the context of clinical trials in patients in whom chemotherapy failed.

Patients with both hypophysitis and LCH may require replacement of anterior and posterior pituitary hormones. DI is managed with desmopressin acetate, a synthetic form of vasopressin. Hypothyroidism is treated with thyroid hormone replacement (levothyroxine); growth hormone deficiency is treated with human recombinant growth hormone (somatotropin); and secondary adrenal insufficiency requires daily corticosteroid replacement and instructions for increased dosing for stress and illness.

Gonadotropin deficiency in adults is treated with appropriate hormone replacement—testosterone for male patients and estrogen replacement for female patients. This should be initiated in adolescents who have either failed to spontaneously undergo puberty or have had arrest of pubertal development after onset.

What are the adverse effects associated with each treatment option?

Common adverse effects of desmopressin acetate include nausea and flushing. Overdose can result in hyponatremia and water intoxication syndrome.

At elevated doses, levothyroxine treatment can result in symptoms of hyperthyroidism, such as tachycardia, tremors, diarrhea, and heat intolerance. Patients with hypophysitis should be thoroughly evaluated for adrenal insufficiency before treatment of hypothyroidism, as levothyroxine treatment can precipitate an adrenal crisis in a patient with untreated adrenal insufficiency.

Common side effects of growth hormone treatment include fluid retention and edema, arthralgias, and headaches. These symptoms tend to resolve with time or decreased dose. Severe adverse events include increased risk of slipped capital femoral epiphysis, impaired glucose intolerance, progression of scoliosis, and benign intracranial hypertension. There is controversy over increased risk of malignancy, based in part on increased risk of secondary malignancy in patients treated for growth hormone deficiency resulting from a primary tumor.

Adverse reactions associated with testosterone include increased blood pressure, acne, alopecia, irritation at application/injection site, gynecomastia, and lipid abnormalities. Androgen treatment can also accelerate closure of epiphyses in growing children; age, height, and degree of skeletal maturation must be taken into account before initiating treatment.

What are the possible outcomes of hypophysitis and Langerhans cell histiocytosis?

In one series of 95 children and adolescents with lymphocytic hypophysitis, 60% had reduction in the size of the pituitary mass over time, 2% had an increase in the size of the pituitary mass, and 29% had no change in the size of the mass. Five percent of patients were subsequently found to have empty sella. Of the 67 children with one or more hormone deficiencies at presentation, 65 required long-term replacement. The outcome in terms of size of the pituitary mass was not related to surgical intervention.

Children with low-risk LCH typically complete treatment with no long-term sequelae. Patients with DI are at long-term risk of persistent DI and panhypopituitarism. Patients with multisystem involvement have a threefold increased risk of long-term problems over those with single-system involvement related to sites of disease involvement. Patients with multisystem disease have a 46% probability of disease reactivation within 5 years of achieving first complete disease resolution.

What causes this disease and how frequent is it?

Both hypophysitis and LCH are presumed to have autoimmune causes. However, specific causes of each disorder are not definitively known. Hypophysitis is a rare disorder, most frequently associated with pregnancy and the postpartum period. The true incidence is unknown because of confusion with Sheehan syndrome and spontaneous recovery of undiagnosed patients. Lymphocytic hypophysitis is significantly more common than either granulomatous hypophysitis or xanthomatous hypophysitis. The incidence of LCH appears to be between 3 and 5 cases/million children.